Sequence-dependent nucleosome sliding in rotation-coupled and uncoupled modes revealed by molecular simulations

Abstract

While nucleosome positioning on eukaryotic genome play important roles for genetic regulation, molecular mechanisms of nucleosome positioning and sliding along DNA are not well understood. Here we investigated thermally-activated spontaneous nucleosome sliding mechanisms developing and applying a coarse-grained molecular simulation method that incorporates both long-range electrostatic and short-range hydrogen-bond interactions between histone octamer and DNA. The simulations revealed two distinct sliding modes depending on the nucleosomal DNA sequence. A uniform DNA sequence showed frequent sliding with one base pair step in a rotation-coupled manner, akin to screw-like motions. On the contrary, a strong positioning sequence, the so-called 601 sequence, exhibits rare, abrupt transitions of five and ten base pair steps without rotation. Moreover, we evaluated the importance of hydrogen bond interactions on the sliding mode, finding that strong and weak bonds favor respectively the rotation-coupled and -uncoupled sliding movements.

Chromatin remodelers couple inchworm motion with twist-defect formation to slide nucleosomal DNA

“…1c). The nucleosome model is the same as that previously employed to study spontaneous nucleosome repositioning (Brandani et al, 2018;Niina et al, 2017), whereas the remodeler model and its interactions with the DNA are based on the cryo-EM structure of the Snf2-nucleosome complex (Liu et al, 2017). Our computational model coarse-grains proteins at the level of individual residues (Li, Wang, & Takada, 2014) and DNA at the level of sugar, phosphate, and base groups, capturing the sequence-dependent flexibilities of base steps Olson, Gorin, Lu, Hock, & Zhurkin, 1998) (see the Materials and Methods section and Refs.…”

“…Indeed, DNA sliding on nucleosomes can also be simply driven by thermal fluctuations (Meersseman, Pennings, & Bradbury, 1992). Modes of nucleosome repositioning can be classified in two types depending on whether sliding is accompanied by the rotation of DNA around its axis (Niina, Brandani, Tan, & Takada, 2017). In the rotation-uncoupled mode, sliding proceeds via large steps of about a DNA turn (~10 bp) (Lequieu, Schwartz, & de Pablo, 2017;Niina et al, 2017;Schiessel, Widom, Bruinsma, & Gelbart, 2001), possibly facilitated by the formation of loops (Lequieu et al, 2017;Schiessel et al, 2001).…”

“…In the rotation-uncoupled mode, sliding proceeds via large steps of about a DNA turn (~10 bp) (Lequieu, Schwartz, & de Pablo, 2017;Niina et al, 2017;Schiessel, Widom, Bruinsma, & Gelbart, 2001), possibly facilitated by the formation of loops (Lequieu et al, 2017;Schiessel et al, 2001). On the other hand, in the rotation-coupled mode, DNA sliding proceeds at small steps of 1 bp via a screw-like motion (Niina et al, 2017), facilitated by the formation of twist defects (Brandani, Niina, Tan, & Takada, 2018;Edayathumangalam, Weyermann, Dervan, Gottesfeld, & Luger, 2005;Kulić & Schiessel, 2003;Richmond & Davey, 2003;Shaytan et al, 2016;van Holde & Yager, 1985). Twist defects are the structural deformations of DNA allowing to accommodate different numbers of base pairs between the strong histone-DNA contact points, which correspond to half-integer SHL locations (Edayathumangalam et al, 2005;Luger et al, 1997).…”

“…Due to the ubiquitous importance of remodelers for chromatin organization, gene expression and replication (Lai & Pugh, 2017), the detailed understanding of their molecular mechanism of action would be extremely valuable. Coarse-grained molecular dynamics (MD) simulations represent an ideal tool for approaching this problem, since their resolution can be high enough to accurately represent the potential key steps occurring during active nucleosome repositioning (Brandani et al, 2018;Flechsig & Mikhailov, 2010;Niina et al, 2017), while achieving a speed-up of several orders of magnitude relative to allatom simulations , for which the system size and the relevant time scales would result in an exceedingly large computational cost. Notably, coarse-graining approaches have been successfully applied to the study of nucleosome dynamics (Chang & Takada, 2016;B.…”

“…Notably, coarse-graining approaches have been successfully applied to the study of nucleosome dynamics (Chang & Takada, 2016;B. Zhang, Zheng, Papoian, & Wolynes, 2016), including spontaneous repositioning (Brandani et al, 2018;Lequieu et al, 2017;Niina et al, 2017), and ATP-dependent molecular motors (Flechsig & Mikhailov, 2010;Koga & Takada, 2006).…”